The purpose of the current study is to develop a mouse model for exploration of the pathogenesis of dengue virus (DENV) infection. HepG2 cells were transplanted to severe combined immunodeficiency (SCID) mice intraperitoneally to develop a HepG2-SCID mouse chimera model. To confirm the successful transplantation , the concentration of human albumin (hALB) in the serum was determined by sandwich enzyme-linked immunosorbent assay. Following challenge with intraperitoneal injection of DENV2, HepG2- SCID mice were evaluated by detection of virus distribution and histological changes in major organs. HepG2 cells engrafted into SCID mouse could support the replication of DENV2. HepG2-SCID mouse showed viremia and severe organ injuries. The data suggest that DENV2-infected HepG2-SCID chimera model is developed successfully , which would provide a useful tool for studying pathogenesis of DENV infection.